The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Cancer is one of the leading causes of death worldwide and accounts for 7.9 million deaths (around 13% of all deaths) in 2014 and with an estimated 13 million deaths in 2030. Over the last 50 years, many molecules have been developed as anticancer reagents against various types of cancers. The majority of anticancer molecules in the clinical world exert their activity by inhibiting cellular processes in normal or cancerous cells. It is important to have significant anticancer molecules with less effect on normal cells and considerable effect on the cancer cells (and targets), which is a major hurdle nowadays. However, a high percentage of them fail clinically due to their lack of selectivity and adverse effects (including toxicity).
Thiosemicarbazones are a class of small molecules that have been evaluated over the last 50 years as antivirals (Arch. Pharm. (Weinheim) 2002, 335, 183-186; Virology 1991, 185, 857-861) and as anticancer therapeutics (Adv. Enzyme Regul. 1999, 39, 3-12), as well as for their parasiticidal action against Plasmodium falciparum (J. Med. Chem. 1979, 22, 855-862). A variety of thiosemicarbazone derivatives have also been reported as anticancer agents, incuding pyrazolone-substituted thiosemicarbazone derivatives (WO 2007/142308), liquiritigenin thiosemicarbazone derivatives (European Journal of Medicinal Chemistry (2010), 45(8), 3453-3458), N,N-diaryl(thio)ureas derirvatives (WO 2010/138820), thio-carbonyl compounds as antitumor agents (CN 101759692), piperazine hydroxamates as histone deacetylase (HDAC) inhibitors (Bioorganic & Medicinal Chemistry Letters (2010), 20(13), 3906-3910), various 3-thylidenehydrazino-substituted heterocyclic compounds (WO 2006/062240) and heteoaryl-thiosemicarbazone and semicarbazone derivatives (WO 2009/079797, WO 2008/083491) as well as pyridinyl-thiosemicarbazides derivatives (CN 1224005).
Moreover, thiosemicarbazones and their metal complexes present a wide range of bioactivities as antimicrobial, anti-tumor, antiviral and antiprotozoal agents (Medicinal Chemistry Research (2013), 22(6), 2802-2808). It was also reported that Pd(II) complexes of certain 1-N-substituted 3-phenyl-2-pyrazoline derivatives (European Journal of Medicinal Chemistry (2008), 43(2), 393-403) and zinc(II) complexes of 2-acetyl pyridine 1-(4-fluorophenyl)-piperazinyl thiosemicarbazone derivatives (Journal of Inorganic Biochemistry (2010), 104(4), 467-476) present cytotoxic activity against MCF-7, TK-10 and UACC-62 human tumor cell lines and were able to induce cell death by apoptosis. Platinum(II) and palladium(II) complexes with 2-acetyl pyridine 4N-ethyl thiosemicarbazone were also shown to overcome cisplatin resistance (BioMetals (2003), 16(3), 411-418).
More recently, certain thiosemicarbazone compounds were also reported to target the metastasis suppressor, NDRG1. NDRG1 inhibits both growth and metastasis as well as angiogenesis of pancreatic cancer in vivo, leading to reduced tumor progression. NDRG1 is also correlated with increased differentiation of pancreatic cancers (Carcinogenesis (2006) 27: 2355-66; Cancer Res (2006) 66: 6233-42). Further, various alkyl piperidine/piperazine thiosemicarbazone compounds were studied for neuron imaging and treatment of various neurodegenerative disease (US 2005/0222166); thiosemicarbazones also represent validated drug leads that kill several species of protozoan parasites through the inhibition of cysteine proteases as well as other novel targets (Journal of Medicinal Chemistry (2004), 47(12), 3212-3219). In addition, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) recently was demonstrated to possess a broad spectrum of activity in animal tumor models and reached clinical phase II as an antineoplastic therapeutic (Invest. New Drugs, 2008, 26, 169-173; Cancer Chemother. Pharmacol. 2002, 50, 223-229; Ann. Oncol., 2009, 20, 1275-1279).
As is readily apparent from the large diversity of activities, thiosemicarbazone and semicarbazone are important pharmacophores for the development of therapeutics. Although many thiosemicarbazones are taught as cancer therapeutic agents (WO 2008/084391, WO 2007/142308; WO 2009/007997; CN103058995, and CN102653521), all or almost all of them suffer from relatively high toxicity, lack of specificity, and/or therapeutic efficiency. Therefore, there is still a need for new and alternative treatments for cancer with less toxicity and increased efficacy.